Our research program focuses on four subject areas: (1) the nature of protection against malaria that is conferred to individuals carrying hemoglobin mutations and red blood cell polymorphisms including but not limited to hemoglobin C, hemoglobin S, hemoglobin E, alpha- and beta-thalassemia, and G6PD deficiency; (2) the nature of infant protection against malaria in the first few months of life, involving cooperative interactions between fetal hemoglobin and maternal-derived immune antibodies; (3) the molecular mechanisms by which malaria-protective polymorphisms reduce the expression of PfEMP-1, the main virulence factor of Plasmodium falciparum, on the surface of parasitized red blood cells; (4) the nature of microvessel inflammation and other pathogenic processes caused by the adherence of parasitized red blood cells to human microvascular endothelial cells and blood monocytes. In each of these areas we seek research advances that can improve the knowledge of fatal disease processes in individuals with malaria and thereby support the development of new antimalarial therapeutics and vaccines that aim to prevent death. The research activities in our program are multidisciplinary and include three field studies in malarious regions of Africa and Asia as well as programs of basic laboratory investigation.